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Role of GRM1 in altering glutamate metabolism and bioavailability

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TitleInfo
Title
Role of GRM1 in altering glutamate metabolism and bioavailability
Name (type = personal)
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Shah
NamePart (type = given)
Raj D.
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Raj D. Shah
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author
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Zhou
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Renping
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Renping Zhou
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Advisory Committee
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chair
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Dreyfus
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Cheryl
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Cheryl Dreyfus
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Advisory Committee
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White
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Lori
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Lori White
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Advisory Committee
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internal member
Name (type = personal)
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Chen
NamePart (type = given)
Suzie
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Suzie Chen
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Advisory Committee
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internal member
Name (type = personal)
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Jin
NamePart (type = given)
Shengkan (Victor)
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Shengkan (Victor) Jin
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Advisory Committee
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outside member
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Rutgers University
Role
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degree grantor
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School of Graduate Studies
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school
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Text
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theses
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DateCreated (encoding = w3cdtf); (keyDate = yes); (qualifier = exact)
2020
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2020-05
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2020
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
Altered metabolic activity has been implicated in several types of cancer including malignant melanoma. Previously, we have illustrated the role of a neuronal receptor, metabotropic glutamate receptor 1 (GRM1), in the neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. The overall goal of this dissertation is to determine how ectopic GRM1 expression leads to the rewiring of metabolic processes, especially in glutamate metabolism, and how this may contribute to deregulated tumor cell proliferation. Using a set of isogenic melanoma cell lines, we demonstrated correlations between GRM1 and glutaminase (GLS) expression. Metabolomics revealed that GRM1+ melanoma cells exhibit elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle-related amino acids and intermediates, especially glutamate. The increased intracellular pool size of glutamate could be a direct result of increased conversion of glutamine to glutamate via the activity of GLS. Furthermore, principle component analysis revealed that modulation of GRM1 in the aforementioned set of isogenic melanoma cells causes metabolic perturbations that overlap with GRM1 expression levels. It has been well known that glutaminolysis is primarily responsible for increased glutamate production in tumors. Using a rational drug-targeting strategy, we critically evaluate metabolic bottlenecks with the goal to cut off tumor glutamate bioavailability. In cultured GRM1+ melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS suppressed cell proliferation while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single agent treatment, restricting glutamate bioavailability and leading to severe suppression of tumor cell proliferation in vitro. Most importantly, disruption of GRM1 signaling through combined actions of CB-839 and riluzole significantly suppressed tumor growth in two independent xenograft mouse models of melanoma, with no obvious symptoms of toxicity detected. Molecular analysis of excised tumor specimens demonstrated enhanced suppression of ERK and AKT phosphorylation with the combination of CB-839 and riluzole. Using LC-MS analysis, we determined that the blood plasma concentration of unbound riluzole is substantially higher in male mice compared to females possibly clarifying why riluzole treatment displays a superior response in males. Finally, we established that GLS overexpression, in GRM1+ cell lines, ensues at least in part, through the deep-rooted mTORC axis, as seen through pharmacological inhibition of mTOR phosphorylation and subsequent downregulation of GLS. These insights, combined with our data, support the rationale to target glutamate bioavailability and may aid in the identification of novel metabolic targets to combat GRM1+ human neoplasia.
Subject (authority = local)
Topic
Glutamate
Subject (authority = RUETD)
Topic
Toxicology
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_10634
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application/pdf
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text/xml
Extent
1 online resource (xi, 114 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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Identifier (type = doi)
doi:10.7282/t3-98zf-ys80
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Shah
GivenName
Raj
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-03-23 15:44:51
AssociatedEntity
Name
Raj Shah
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Type
Embargo
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2020-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2022-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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